The onset of stroke is usually sudden, but the pathological processes leading up to it and recovery from it are gradual. This renewal application, "Mechanisms of Injury and Repair in Ischemic Stroke", focuses on the humoral and cellular mediators of ischemic brain injury and repair. The term "humoral mediator" connotes the long term effects of cytokines hormones, and growth factors. In Project 1 the influence of chronic hyperviscosity on recurrent stroke will be examined in a longitudinal clinical study. This project will determine whether impaired glucose tolerance and/or chronic release of interleukins 1 or 6 predisposes to hyperviscosity. Project 2 will examine the influence of dexamethasone on brain metabolism in ischemia using in vivo and in vitro models. A key question to be addressed is whether dexamethasone increases glucose transport into the brain, thereby aggravating brain lactic acidosis during ischemia. Project 3 will use animal models of ischemia and molecular biological techniques to investigate the role of acidic and base fibroblast growth factors in central nervous system repair after ischemic injury. The experiments proposed will study the regional distribution, cellular sources, and biochemical signaling and production of these growth factors in the brain. Project 4 will examine cellular mechanisms of nervous system repair in the mouse cerebellar explant culture system. Studies in this project will define the role of neuronal activity in neuronal-cellular and neuronal-glia reorganization after injury. The proposed projects, focusing on humoral and cellular modulators, range from molecular to clinical neuroscience and offer potential therapeutic benefits for stroke prevention, intervention, and rehabilitation.